OBJECTIVES: Tyrosine kinase inhibitors (TKIs) revolutionized chronic-myeloid-leukemia in chronic-phase (CML-CP) treatment, however, long-term benefit depends on treatment tolerability, quality-of-life (QOL) improvement, and sustained deep-molecular-response (DMR), which will allow patients to be eligible for treatment-free-remission (TFR) in future. This systematic-literature-review summarizes clinical evidence in front-line CML-CP.

METHODS: Electronic databases and grey-literature were searched for clinical-trials published until 12-October-2023 for evidence on clinical-efficacy and QOL with an extension to observational studies published until 08-February-2024 for TFR.

RESULTS: Overall, 34 studies were included, out of which twelve randomized-clinical-trial studies reported outcomes on efficacy and safety, and two on QOL. Twenty-two observational and non-randomized studies reported TFR.

Evidence on response-rates consistently favoured bosutinib (12-months, range of major-molecular-response (MMR): 41.0%-47.2%; MR4.5: 6.1%-8.1%), dasatinib (23.6%-81.8%; 14.3%-35.2%) and nilotinib (44.0%-52.2%; 2.6%-6.9%) versus imatinib (22.0%-39.0%; 3.3%-15.0%). Overall-survival rates were similar across treatments, reported at different time-points. Safety outcomes were comparable across all treatments; however, adverse-event (AE) related treatment-discontinuation was higher with bosutinib (AEs: increased alanine-aminotransferase/aspartate-aminotransferase, thrombocytopenia, neutropenia, vomiting, increased lipase and pleural effusion) and dasatinib (AEs: pleural effusion and drug-related cytopenia) versus imatinib (AEs: increased alanine-aminotransferase, thrombocytopenia, neutropenia, and myalgia) (13.8%-19.0%, 5.0%-13.0% versus 1.5%-10.0%). QOL scores for bosutinib, nilotinib, and imatinib with FACT-Leu, EQ-5D, and SF-36 showed improvement without clinically-meaningful change-from-baseline.

Studies evaluating TFR reported varying patient eligibility criteria. Most common TFR-eligibility criteria were treatment duration >3 years and sustained MR4.5 for ≥2 years with follow-up till loss-of-MMR after treatment discontinuation. At 12 months, patients in TFR varied from 59.2% for dasatinib to 76.5% for nilotinib.

CONCLUSIONS: Reportedly dasatinib, nilotinib, and bosutinib are more effective than imatinib in front-line CML-CP, but AE-related treatment-discontinuation is lower with imatinib and nilotinib. Evidence suggests that initiating TFR benefits patients by controlling disease progression without treatment and eliminates treatment-related-AEs. Further research is needed to compare overall incremental and sustained benefit of TKIs as front-line CML-CP treatment.